Introduction
Although tumor necrosis factor (TNF) antagonists are highly effective agents for the treatment of rheumatoid arthritis (RA), a subset of patients with RA may be intolerant to one of these agents or may experience an inadequate response or a loss of response over time [
1‐
8]. A relevant clinical question, particularly as non-anti-TNF biologics have become available for RA therapy, is whether switching to a different TNF antagonist would be effective when the first has failed or resulted in intolerance [
9]. Clinical reports to date demonstrated that a switch from one TNF antagonist to another is safe and effective [
10‐
23]. Failure in effectiveness is recommended to be specified as an initial lack of response or loss of an initial response over time [
16]. The formation of antibodies against infliximab (IFX) has been found to reduce the effectiveness of IFX over time [
24].
This pilot study investigated the effectiveness and safety of adalimumab in patients with RA who had been treated previously with IFX and experienced treatment failure owing to no response, loss of response, or intolerance. The impact of anti-IFX antibodies on the subsequent therapy with adalimumab was also examined.
Materials and methods
Patients
This prospective open-label study included men and women ≥18 years of age who met the American College of Rheumatology (ACR) criteria for the diagnosis of RA for at least 6 months, had active RA as defined by the 28-joint Disease Activity Score (DAS28) ≥3.2 at study entry, and had previous use of IFX defined as administration of at least four infusions. The reasons for discontinuation of IFX were collected as no response, loss of response, or intolerance (i.e., infusion reactions) based on the investigator’s assessment. Patients who discontinued IFX owing to adverse reactions other than intolerance were not allowed to enter the study. Additional exclusion criteria encompassed prior treatment with alkylating agents, intravenous immunoglobulin, or any investigational agent within 30 days or five half-lives (whichever was longer); IFX within the last 8 weeks; more than one disease-modifying antirheumatic drug (DMARD) or DMARD combination after IFX treatment; biologic RA therapies other than IFX; total lymphoid irradiation; history of malignancies; inflammatory joint disease other than RA; uncontrolled medical conditions (e.g., diabetes and congestive heart failure); active tuberculosis (TB), histoplasmosis, listeriosis, positive serology for hepatitis B or C, or human immunodeficiency virus; persistent infection or severe infection requiring hospitalization or recent treatment with intravenous or oral antibiotics; previous diagnosis or signs of central nervous demyelinating diseases; pregnancy; or breastfeeding.
If patients had chest radiographs indicative of prior TB infection or a positive purified protein derivative (PPD) tuberculin skin test, appropriate prophylactic anti-TB therapy had to be initiated before entering the study.
The protocol was approved by an independent ethics committee at participating sites, and written informed consent was obtained from all patients.
Study design
This was a 16-week open-label study that was followed by maintenance therapy for up to 56 weeks. After a screening period of at least 3 days (to allow for assessment of the PPD tuberculin skin test administered at the study entry visit), all patients self-administered adalimumab 40 mg subcutaneously every other week (eow) in addition to their pre-existing antirheumatic therapy. Doses of DMARDs, glucocorticoids (prednisone equivalent ≤10 mg/day), and/or nonsteroidal anti-inflammatory drugs that patients may have been taking at study entry were to remain stable until Week 16. Patients were to be withdrawn from the study if they did not show adequate response to study treatment at Week 16 (less than 20% reduction in tender joint count [TJC] and/or swollen joint count [SJC] compared with study entry). Addition of further DMARDs was not allowed.
Effectiveness, pharmacokinetic, and safety evaluations
Patients were assessed at screening, and then at baseline, Weeks 2, 8, and 16, and every 8 weeks thereafter through Week 56. Effectiveness assessments included the change in DAS28 compared with study entry and both European League Against Rheumatism (EULAR) and ACR response criteria, the Health Assessment Questionnaire Disability Index (HAQ DI), and acute-phase reactants. The effectiveness results of Week 16 were considered primary.
Adverse events (AEs) were collected at each visit after the first adalimumab injection up to 70 days after the last injection.
Serum concentrations of adalimumab were analyzed at baseline and at Weeks 16, 40, and 56 using a validated enzyme-linked immunosorbent assay (ELISA) method by Abbott Laboratories. The lower limit of quantitation (LLOQ) for adalimumab was established at 31.3 ng/ml in undiluted serum. Antiadalimumab antibody (AAA) was measured at study entry and at Weeks 16, 40, and 56 using a validated double-antigen ELISA. The LLOQ for AAA was established at 5 ng/ml in undiluted serum. A positive antiadalimumab signal was defined as a concentration exceeding 20 ng/ml that could not be suppressed by ≥50% after the addition of 10% human serum to the sample. Human antichimeric antibody (HACA; i.e., anti-IFX antibodies) and serum IFX concentrations status were determined at baseline using ELISA methods. Because the presence of adalimumab interferes with the serum IFX ELISA assay, HACA and serum IFX concentrations were not assessed beyond baseline.
Statistical analysis
The sample size of this open-label pilot study was based on practical rather than biometric considerations. Both the effectiveness and safety analyses were performed on the set of patients who received at least one injection of adalimumab. Subgroup analyses for effectiveness endpoints also were performed by reason for discontinuation of IFX and by HACA status at baseline. In the case of discontinuation of IFX owing to no response or loss of response, patients were counted in the corresponding group regardless of whether they had an additional cause of intolerance, whereas the IFX discontinuation owing to intolerance subgroup was exclusive.
Effectiveness analysis consisted of summary statistics and confidence intervals with last-observation-carried-forward methods applied. Pharmacokinetic analysis consisted of descriptive statistics.
Discussion
In accordance with other reports about successful switching from one TNF antagonist to another, the results of this study indicate that patients with RA who had previously discontinued treatment with IFX experienced clinically meaningful improvements in all effectiveness endpoints with adalimumab treatment [
10‐
15,
17‐
19]. The patients who reported a loss of response under IFX treatment appeared to experience the greatest effectiveness with adalimumab by several disease-response measures, followed by the small patient subset that had been intolerant to IFX. The patients with no response to their previous IFX therapy had somewhat lower response rates to adalimumab. Similar results were recently published in another open-label study in a large patient cohort who switched from prior anti-TNF therapy to adalimumab [
18]. The documentation of reason for discontinuation of IFX is limited, as there was no other criterion but the investigator’s clinical assessment.
Interestingly, patients with a reported initial lack of response to IFX had the lowest mean DAS28 value and lowest joint counts at baseline among the subsets by reason of IFX discontinuation, whereas the mean HAQ DI at baseline was worst in these patients. However, most of the recent publications either from registers or from clinical studies on switching among TNF antagonists are based on the physician’s discretion when the reasons for discontinuation are reported [
17‐
19].
Results of subgroup analyses by patient’s baseline HACA status (available for 32 of the 41 patients) indicate that adalimumab is effective and well-tolerated in patients who may have developed HACA with prior IFX treatment. The low ACR50 and ACR70 and good EULAR response rates at Week 16 in patients with negative HACA appear to be more likely related to confounding baseline characteristics, such as a greater percentage of patients who had experienced no response to IFX and a longer RA duration compared with patients with positive HACA status. However, beyond Week 16, the response rates in the HACA-negative subset increased and even surpassed the rates achieved by HACA-positive patients.
Results of the pharmacokinetic analysis indicate that, for the majority of patients, the mean steady-state serum adalimumab trough concentrations achieved with the recommended regimen of 40 mg eow were near or above 4 to 8 µg/ml, which is consistent with what has been observed in other pharmacokinetic trials of adalimumab in patients with RA [
26,
27]. These concentrations are three to seven times the average effective concentration in 50% of patients for TJC, SJC, and numeric ACR [
27]. Although mean serum adalimumab trough concentrations appeared to be lower in patients with measurable HACA at baseline, the potential for interference of HACA with the serum adalimumab assay has not been evaluated. In general, the mean and median serum adalimumab concentrations were greater in patients who concomitantly received methotrexate. In a recent study in 121 patients with RA treated with adalimumab, good responders had greater adalimumab serum concentrations than nonresponders, and the formation of AAA (present in 21/121) was reduced in patients who received concomitant methotrexate [
28]. AAAs were detected in two of the patients in this analysis, both were not receiving concomitant DMARDs and both had a positive HACA status at study entry. In previous clinical adalimumab trials, AAA had been documented in 12% of the patients and was not found to have an impact on the efficacy of adalimumab [
29].
Adalimumab was generally well-tolerated in this selected population, and safety results did not suggest any new signals with regard to the safety of the drug. In particular, no additional risks for allergic reactions under adalimumab were found in these 41 patients with a history of intolerance to IFX.
In the two patients diagnosed with lymphomas (cutaneous T cell lymphoma in one and a B cell lymphoma in the other), exposure to adalimumab was ≤1 year. The total exposure to anti-TNF therapy and the previous extensive immunosuppressive treatment for RA together in these patients represent a risk for the development of lymphoma.
Limitations of our study include the small number of patients in each subgroup and the nonrandomized study design.
The results of this pilot study indicate that adalimumab is generally effective and well-tolerated for the treatment of RA in patients who have failed IFX therapy, including those who have developed HACA for IFX.
Acknowledgments
The authors thank the physicians and staff members of all study centers for having participated in this study. In addition, we thank Susan Paulson, PhD, for the performance of pharmacokinetic analyses, and Angela Cimmino, PharmD, who provided writing assistance on behalf of Abbott Laboratories. The study was sponsored by Abbott Laboratories.